Nitric oxide (NO) is one of the smallest and simplest of the biologically active molecules in nature. Moreover, NO appears to be one of the most ubiquitous molecules in mammalian species. As one of the most widespread signalling molecules, NO is a major player in controlling nearly every cellular and organ function in the body. NO is the only endogenous molecule able to function as a neurotransmitter, autacoid, constitutive mediator, inducible mediator, cytoprotective molecule, and cytotoxic molecule.
Because NO plays multiple physiological roles in regulating numerous and diverse organ functions, defects in the NO pathway lead to the development of many different pathological conditions. These disorders include hypertension, atherosclerosis, coronary artery diseases, cardiac failure, pulmonary hypertension, stroke, impotence, vascular complications in diabetes mellitus, gastrointestinal ulcers, asthma, and other central- and systemic-nervous system disorders.
All nitric oxide donors (NODs) share the common property of producing NO-related activity when applied in biological systems and thus mimic endogenous NO responses. However, the pathways leading to NO formation/release differ significantly among the compound classes, as do their chemical reactivities. Whereas some compounds require enzymatic catalysis, others produce NO non-enzymatically. In some compounds, the liberation of NO is preceded by a reduction or an oxidation. The process is complicated still more by the specific susceptibility of compounds to the changes in pH, oxygen, light and temperature and by the different by-product formation that takes place during the decomposition or the metabolism. In addition, the kinetics of NO release from a given compound is often more important than the absolute amount of NO released. Moreover, the tissue distribution of the NODs and the site where NO is generated is also of great importance. All these considerations are important since they explain the very different pharmacological profiles obtained with the different NODs described in the literature and make it necessary to fully characterize the pharmacological profile of newly developed NODs in research and development.
Pharmaceutically useful NODs having a isosorbide-mononitrate skeleton are disclosed in WO 00/20420. The compounds as such disclosed therein do not form part of the present invention. That application describes organic nitrates capable of providing a potent vasodilating effect and which at the same time show a small or null tolerance effect. However, no indication exists for the possible use of said compounds for the treatment of platelet activation; thrombosis; stroke; tissue damage due to ischemia and/or to ischemia/reperfusion; pathological conditions where oxidative stress plays an important role in their pathogenesis; and/or atherosclerosis. Accordingly the new use of said compounds forms part of the present invention.
One of the principal problems of the nitrated organic compounds described in the literature and those used clinically resides in the fact that their mechanism of action is the relaxation of vascular smooth muscle without modifying other pathologic processes involved in cardiovascular diseases.
Tissue ischemia results in the depletion of intracellular adenosine triphosphate (ATP) stores, which subsequently compromises the function of membrane-associated, ATP-dependent ionic pumps in endothelial cells. This membrane dysfunction allows entry of calcium, sodium, and water into the cells. The resultant accumulation of calcium and other ions in the cell can result in cell swelling and the inappropriate activation of cellular enzymes. One enzyme that is activated by the rise in intracellular calcium during ischemia is xanthine dehydrogenase (XDH). Under normal conditions, hypoxanthine (a breakdown product of ATP metabolism) is oxidized by XDH, in an NADPH-dependent manner, to produce xanthine and uric acid. However, during the hypoxic condition of ischemia, hypoxanthine levels rise within the cell due to ATP hydrolysis, and there is a calcium-dependent activation of proteases that convert the NADPH-reducing XDH to an oxygen-reducing form of the enzyme, namely, xanthine oxidase (XO). On restoration of blood flow (reperfusion) to the tissue and with the reintroduction of molecular oxygen, XO will convert hypoxanthine to xanthine and uric acid, and it will catalyze the reduction of molecular oxygen to form both superoxide anion radicals (O2−) and hydrogen peroxide (H2O2). This XO-dependent mechanism of oxygen radical production has been invoked to explain the involvement of O2− and H2O2 in reperfusion injury to a variety of organs, including intestine, brain, heart, and skeletal muscle.
The generation of oxygen radicals in postischemic tissues appears to overcome the capacity of endogenous antioxidants such as superoxide dismutase (SOD), catalase, glutathione to protect endothelial and parenchymal cells. Exogenous antioxidants such as SOD and catalase have been shown to attenuate the leukocyte infiltration and tissue injury elicited by ischemia and reperfusion.
Nitric oxide bioavailability appears to be reduced in reperfusion, which is likely due to a decline in endothelial NO production and an increased inactivation of NO by endothelial-cell-derived O2−. The limited bioavailability of NO contribute to the abnormal cell-cell interactions and vascular dysfunction during reperfusion. Nitric oxide-donating compounds have shown promise as protective agents in experimental models of ischemia-reperfusion. However, considering the processes involved in the damage by ischemia-reperfusion it would be of great interest to have a molecule with both properties: being a NO-donor and at the same time with antioxidant properties.
Atherosclerosis is an active process initiated by a continuous damage of the vascular endothelium. The view of atherosclerosis as a response to a damage of the endothelium was developed when the association of atherosclerosis with risk factors (high LDL plasma levels, low HDL plasma levels, hypertension, oxidative stress, tobacco consumption, diabetes mellitus, high Lp(a) plasma levels or modification of LDL such as oxidation or glycation that prevent LDL removal by the specific receptors) was studied. LDL accumulates in the vascular wall as a consequence of a vascular-endothelial cells active transport. During this process, the LDL suffers the oxidation of a part of the molecule. The presence of oxidated-LDL (ox-LDL) is of capital importance in the development of the atherosclerotic lesion. To the same extent, the theory that oxidized LDL is responsible for some of the pathological features of atherosclerotic lesions derives from the findings in cultured cells systems that oxidized LDL causes cellular changes that correlate with known aspects of arterial lesions but are not induced by native LDL. Endothelial injury, LDL retention in intimal interstitium, monocyte recruitment into intima, engorgement of macrophages with lipoprotein-derived lipid, smooth muscle cell migration and proliferation, accumulation of necrotic cell debris, and tendencies towards vasoconstriction and procoagulant activity are characteristics of atherosclerosis.
Cardiac allograft vasculopathy is an unusually accelerated and diffuse form of coronary atherosclerosis that limits the long-term success of cardiac transplantation. Coronary endothelial vasodilator dysfunction is a common and early marker for the development of cardiac allograft vasculopathy.
Accordingly, novel nitrated organic compounds which, in addition to the vasodilating activity, could combine activities that would allow them to modify other pathologic processes involved in cardiovascular diseases, such as atherosclerosis and tissue damage due to ischemia and/or due to ischemia and reperfusion, will represent an important advantage with respect to the compounds nowadays in use.